The broad, long-term goal of the proposed studies is to provide a precise molecular basis of how particular biophysical signatures endowed to antibodies correlate to antibody-dependent cellular cytotoxicity (ADCC) induction, which appears to confer protection against HIV infection and inhibits disease progression. To do so, we will address two Specific Aims: (1) to determine the biophysical basis of interactions between antibodies and Fc receptors that lead to increased induction of ADCC in elite controller populations relative to individuals with chronic progressive disease;and (2) to determine the structural and energetic bases for how differential antibody glycosylation results in increased ADCC induction and HIV protection. We have recently produced experimental evidence showing: (i) that antibodies generated by HIV elite controllers bind to the Fc?RIIIa receptor with significantly higher affinity than antibodies generated by chronically infected individuals;(ii) that antibodies from chronically infected individuals bind with increasingly weaker affinity to Fc?RIIIa throughout the early stages of HIV infection;and (iii) that a panel of broadly neutralizing HIV antibodies exhibits widely varying affinities to Fc?RIIIa. Each of these results correlates to functional readouts of ADCC induction. Our findings indicate that there exists an entirely novel and previously unrecognized biophysical signature of antibodies produced during HIV infection that correlates to immunological protection. These data suggest a unique opportunity to develop novel HIV vaccine technologies that rationally harness ADCC function to control viral replication. We hypothesize that the ADCC-inducing properties of antibodies generated by elite controllers protect these individuals from disease progression and that recapitulation of the biophysical characteristics of these antibodies in at-risk individuals via novel vaccination strategies will confer broad protection against HIV infection. PROJECT NARRATIVE. More than 30 million individuals are currently infected with human immunodeficiency virus (HIV)-1 worldwide, and in the year 2007 alone 2.7 million additional individuals were infected with the virus and a further 2 million individuals died of AIDS. While relatively effective anti-retroviral therapy exists, it is widely available only in first world countries, and some 95 percent of HIV-1-infected individuals reside in the developing world, and thus, the development of an effective HIV-1 vaccine remains an outstanding global health goal. Our proposed studies are aimed at elucidating critical molecular mechanisms of antibody-dependent cellular cytotoxicity (ADCC) by which the immune systems of some individuals may be controlling HIV infection and progression to AIDS to drive innovation in HIV vaccine design.